Characterization and biological significance of corticosteroid 11 beta-dehydrogenase, the oxidizing component of 11 beta-hydroxysteroid dehydrogenase.
Characterization and biological significance of corticosteroid 11 beta-dehydrogenase, the oxidizing component of 11 beta-hydroxysteroid dehydrogenase.
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皮质类固醇 11 β-脱氢酶（11 β-羟基类固醇脱氢酶的氧化成分）的特征和生物学意义。
DOI：
10.1111/j.1749-6632.1990.tb34280.x
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发表时间：
1990
影响因子：
5.2
通讯作者：
Monder,C
中科院分区：
文献类型：
--
作者：
Monder,C
所有生物活性的糖皮质激素都是1LP-羟基化的。酶催化氧化成1 1-0x0形式会使它们失活；当1 1-0x0基团再次被还原时，生物效力就会恢复。*这一可逆过程的中介是1 LP-羟基类固醇脱氢酶(1 LP-HSD)，这是一种广泛存在于动物组织中的酶。2到目前为止，试图将有意义的生物学作用归因于这种酶，还没有对它在特定组织中的功能提供深入的了解。我们重新检查了描述1LP-HSD的文献，并得到了我们自己的研究的支持，导致我们提出1IP-HSD的行为与单一可逆酶的行为不一致。我们提出了一个替代模型(图1)，在该模型中，观察到的11-0x0和1-Lp-羟基的净相互转化是独立的1-LP-脱氢酶(1 1-DH)和11-氧还原酶(1 1-OR)活性作用的结果。这两种活性都是膜结合的。我们认为11-DH和11-OR在内质网中的位置是该模型的一个重要组成部分，4因为它提供了一个物理结构，在其中酶的活性是协调的。我们最近回顾了支持我们的观点的证据，即ILP-HSD的活性是11-DH作用的净效应的结果，其平衡常数强烈有利于氧化，而其对应的11-OR有利于反向反应。我们的结论部分是基于(1)组织之间氧化/还原比率的巨大变化；(2)竞争性抑制剂选择性地延缓氧化或还原；(3)氧化还原比率在出生前和出生后的发育过程中的变化。对联系温度和酶速度的Arrhenius图的分析表明，1 1-OR的激活能不连续，但不是1 1-DH7(图2)。Arrhenius图谱的解释表明，1 1-DH和1 1-OR在内质网内处于不同的环境中。*在大鼠肝脏中，11-OR通常比1 1-DH更活跃，但由于其更不稳定，很快就完全失活。当膜被改变磷脂结构的处理(如洗涤剂或磷脂酶)干扰时，镶嵌在微粒体基质中的大鼠肝脏1 1-DH的活性经常以非特异性的方式显著增加。这种潜伏释放过程不会在1 1-OR中发生。磷脂酶失活1 1-OR的能力与这两种活性存在于不同的基质环境中的证据一致。所描述的一项原创工作得到了美国公共卫生服务拨款DK-37094的支持。
All biologically active glucocorticoids are 1 lp-hydroxylated. Enzyme catalyzed oxidation to the 1 1-0x0 form inactivates them; biological potency is restored when the 1 1-0x0 group is again reduced.* Mediation of this reversible process has been attributed to 1 lp-hydroxysteroid dehydrogenase (1 lp-HSD), an enzyme widely distributed in animal tissues. 2 Attempts to attribute a meaningful biological role to this enzyme have thus far not provided insight into its function in specific tissues. Our reexamination of the literature describing 1 lp-HSD, bolstered by our own studies, has led us to propose that the behavior of 1 IP-HSD is inconsistent with that of a single reversible enzyme. We are presenting an alternative model (FIG. 1) in which the observed net interconversion of the 11-0x0 and 1 lp-hydroxy groups is the consequence of the action of independent 1 lp-dehydrogenase (1 1-DH) and 11-oxoreductase (1 1-OR) a~ tivities.~ Both activities are membrane bound. We consider the location of 11-DH and 1 1-OR within the endoplasmic reticulum to be an important component of the model, 4 because it provides a physical structure within which the activities of the enzymes are coordinated. We recently reviewed the evidence supporting our view that the activity of Ilp-HSD is the consequence of the net effects of the actions of 11-DH with an equilibrium constant strongly favoring oxidation, and 1 1-OR, its counterpart, favoring the reverse reaction. Our conclusions are based in part on (1) the great variation of oxidation/reduction ratios between tissue^;^(2) selective retardation of oxidation or reduction by competitive inhibitors $ and (3) changes in oxidation1 reduction ratios during pre-and postnatal de~ elopment.~ Analysis of Arrhenius plots, which relates temperature and enzyme velocity, shows discontinuities in the energy of activation for 1 1-OR, but not 1 1-DH7 (FIG. 2). The Arrhenius profiles are interpreted to signify that 1 1-DH and 1 1-OR are in different environments within the endoplasmic reticulum.* In rat liver, 11-OR, frequently more active than 1 1-DH initially, is rapidly and completely inactivated because of its greater lability. The activity of rat liver 1 1-DH embedded in the microsomal matrix often increases significantly in a nonspecific manner when the membrane is perturbed by treatments that alter the phospholipid structure, for example, detergent or pho~ pholipase.~ This process of latency release does not occur with 1 1-OR. The ability of phospholipases to inactivate 1 1-OR, but not 1 1-DH, is in accord with the evidence that the two activities are present in different matrix environments. a Original work described was supported by US Public Health Service grant DK-37094.